Inhalation composition containing lactose pellets

ABSTRACT

The present invention relates to a pharmaceutical composition which is suitable for the administration of medicaments by inhalation. In particular, the pharmaceutical composition comprises microfine particles of medicament and at least one lactose pellet having a diameter of from about 10 to about 1500 micrometers, which pellet comprises a plurality of microfine lactose particles. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of medicament selected from the group consisting of anti-allergics, bronchodilators, anti-inflammatory steroids and mixtures thereof in the pharmaceutical composition as defined is also described.

This application is a 371 of PCT/EP95/00917 filed Mar. 13, 1995.

The present invention relates to an improved pharmaceutical composition,in particular a powder composition suitable for inhalation.

Numerous medicaments, especially those for the treatment of respiratoryconditions such as asthma, are administered by inhalation. Since thedrug acts directly on the target organ much smaller quantities of theactive ingredient may be used, thereby minimising any potential sideeffects caused as a result of systemic absorption. The efficacy of thisroute of administration has been limited by the problems encountered inmaking appropriate and consistent dosages available to the lungs. Thedelivery systems currently available are pressurised metered doseinhalers, nebulisers and dry powder inhalers.

Metered dose inhalers require good coordination of actuation andinhalation in order to achieve consistent dose administration; thiscoordination may be difficult for some patients. Nebulisers areeffective but are relatively expensive and bulky and as a result aremainly used in hospitals. A variety of dry powder inhalers have beendeveloped and, since dry powder inhalers rely on the inspiratory effectof the patient to produce a fine cloud of drug particles, thecoordination problems associated with the use of metered dose inhalersdo not apply.

It has been found that medicaments for administration by inhalationshould be of a controlled particle size in order to achieve maximumpenetration into the lungs, preferably in the range of 1 to 10micrometers in diameter. Unfortunately, powders in this particle sizerange, for example micronised powders, have a high bulk volume and havevery poor flow characteristics due to the cohesive forces between theindividual particles. These characteristics create handling and meteringdifficulties during manufacture of the medicament powder and, mostimportantly, adversely affect the accurate dispensing of the powderwithin the inhalation device. A number of proposals have been made inthe literature to improve the fluidity of dry powder pharmaceuticalformulations.

GB1520248 describes the preparation of soft pellets of finely powderedsodium cromoglycate which have satisfactory fluidity within thereservoir of the inhaler device but have sufficiently low internalcoherence to break up into finer particles of medicament when introducedinto the turbulent air stream in the mouthpiece of the device. Numerousother published patent applications suggest the use of carriermaterials, for example GB1402423, particularly of coarser carriers withparticles having sizes falling within a given range, for exampleGB1242211, GB1381872, GB1410588, GB1478020 and GB1571629. More recentlyWO87/05213 describes a carrier which comprises a conglomerate of one ormore solid water-soluble diluents and a lubricant, EP-0260241 describesa lipid-based dry powder composition and U.S. Pat. No. 5,143,126describes a method of preparing flowable grain agglomerations offormoterol and lactose. Unfortunately the selection of the particle sizeof the drug and excipient and of the ratio of drug to excipientinevitably involves a compromise between adequate bulk and flowproperties for metering and the desired redispersability of fineparticle drug in the inhaled air flow.

According to the present invention there is provided a pharmaceuticalpowder composition suitable for inhalation which comprises microfineparticles of medicament and at least one lactose pellet having adiameter of from about 10 to about 1500 micrometers, which pelletcomprises a plurality of microfine lactose particles.

The particle size of the “microfine” particles of medicament and lactoseshould be such as to permit substantially all of the particles to bepotentially available for inhalation into the lungs upon administrationof the powder composition. Thus, for example, at least 90%, preferablyat least 95% by weight of the particles will have a diameter of lessthan 15 micrometers, preferably in the range of 1 to 10 micrometers, forexample 1 to 5 micrometers.

Medicaments which may be administered in the powder compositionsaccording to the invention include any drugs usefully delivered byinhalation for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonideor fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamime, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutalin; isoetharine, tulobuterol,orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament.

Particularly preferred medicaments for administration using powdercompositions in accordance with the invention include anti-allergics,bronchodilators and anti-inflammatory steroids of use in the treatmentof respiratory disorders such as asthma by inhalation therapy, forexample cromoglycate (e.g. as the sodium salt), salbutamol (e.g. as thefree base or as the sulphate salt), salmeterol (e.g. as the xinafoatesalt), terbutaline (e.g. as the sulphate salt), reproterol (e.g. as thehydrochloride salt), beclomethasone dipropionate (e.g. as themonohydrate), fluticasone propionate or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol.Salmeterol, salbutamol, fluticasone propionate, beclomethasonedipropionate and physiologically acceptable salts and solvates thereofare especially preferred.

It will be appreciated by those skilled in the art that the powdercompositions according to the invention may, if desired, contain acombination of two or more active ingredients. Medicaments may beselected from suitable combinations of the medicaments mentionedhereinbefore. Thus, suitable combinations of bronchodilatory agentsinclude ephedrine and theophylline, fenoterol and ipratropium, andisoetharine and phenylephrine formulations.

Other powder compositions may contain bronchodilators such as salbutamol(e.g. as the free base or as the sulphate salt), salmeterol (e.g. as thexinafoate salt) or isoprenaline in combination with an antiinflammatorysteroid such as a beclomethasone ester (e.g. the dipropionate) or afluticasone ester (e.g. the propionate) or a bronchodilator incombination with an antiallergic such as cromoglycate (e.g. the sodiumsalt). Combinations of isoprenaline and sodium cromoglycate, salmeteroland fluticaseone propionate, or salbutamol and beclomethasonedipropionate as especially preferred.

The final powder composition desirably contains 0.1 to 90% w/w,preferably0.5 to 75% w/w, especially 1-50% w/w, of medicament relativeto the weight of the lactose pellets.

The internal strength or coherence of the lactose pellets of use in thepresent invention may be high (“hard” lactose pellets) or low (“soft”lactose pellets) or a mixture of “hard” and “soft” pellets. However, apreferred embodiment of the invention contains “soft” lactose pelletswith a low internal coherence. These lactose pellets are friable andhave an internal coherence such that the pellets remain substantiallyintact under conditions of packaging, transport, storage and whenfluidised within a container in the inhalation device from which it isintended to dispense the composition according to the invention e.g.unit dose container or bulk reservoir and yet may be disrupted intoindependent microfine lactose particles upon egress into the turbulentair stream within the mouthpiece of the inhaler device. The coherence orstrength of the pellets may be determined by methods known to thoseskilled in the art, for example by a simple strength test such as thatdescribed in GB1520247. Preferred lactose pellets have a crushing weightof between 50 and 500 mg, preferably between 50 and 200 mg, especiallybetween 50 and 100 mg, when measured in accordance with the crushingtest described herein.

The lactose pellets optionally contain one or more conventionalpharmaceutically acceptable ingredients such as diluents, binders,solvents, surfactants, colouring and flavouring agents. However, thelactose pellets preferably consist essentially of microfine lactoseparticles.

The lactose pellets maybe prepared by dry or wet pelleting methods knownin the art. Thus, for example, microfine lactose particles may be drypelleted using a tumbling or agitation process known as“balling”, forexample as described in U.S. Pat. No. 5,143,126. Alternatively,microfine lactose particles may be wet pelleted by tumbling in acontainer together with a minimal amount of liquid (see for example,review by C. Orr (1966), Particulate Technology, Chapter 9, publishedMcMillan, New York). Suitable liquids wet the lactose particlesadequately without dissolving them and have a sufficiently low boilingpoint to ensure rapid evaporation from the pellets thus formed and maybe selected from, for example, alkanes, halogenated alkanes, alcohols,esters and ethers. Suitable liquids include, for example cyclohexane,n-hexane, chloroform, methylene chloride, CFC-113, methanol, ethanol,isopropanol, ethyl acetate and acetone and mixtures thereof. Lactosepellets may also be prepared, for example by controlled agglomeration ina fluidised bed or by spray drying a slurry of the lactose particles.

The preparation and storage of lactose pellets is desirably carried outunder anhydrous conditions to obviate any adverse effects of freemoisture on the strength of the lactose pellets. Lactose is generallyutilised in the form of its monohydrate, which solvate containsapproximately 5% w/w bound water. Desirably, the lactose pellets aresubstantially free of unbound water (free moisture), for examplecontaining less than 1%, particularly less than 0.1% by weight ofunbound water. The use of anhydrous lactose particles may be preferred.

Once formed, the lactose pellets may be admixed with microfine particlesof one or more medicaments, optionally together with one or moreconventional pharmaceutically acceptable ingredients, using conventionaltechniques to prepare the powder compositions according to theinvention.

In one preferred embodiment of the invention the microfine medicamentparticles are coated onto the lactose pellets while tumbling, either asa fine powder, liquid suspension or solution of medicament. Coating witha liquid suspension of medicament particles by a process known as“layering” is preferred. Thus, the lactose pellets may be tumbled with adispersion of microfine medicament particles in a suitable low boilingpoint, non-solublising liquid, such as an alkane, halogenated alkane,alcohol, ester or ether. Suitable liquids will vary according to themedicament used but may include, for example, cyclohexane, n-hexane,chloroform, methylene chloride, CFC-113, methanol, ethanol, isopropanol,ethyl acetate and acetone and mixtures thereof.

Suitably a low wetting volume, for example 0.6:1 v/w liquid:medicamentpowder is employed in the layering process to prepare coated pellets.However, such concentrated suspensions of certain medicament and liquidcombinations may be too viscous to be layered in this manner and it maybe necessary and/or desirable to prepare coated pellets by continuous orintermittent spraying of a more dilute medicament suspension onto thelactose pellets under conditions of controlled evaporation.Alternatively, the lactose pellets may be slurried or sprayed with asuspension of medicament in a suitable non-solubilising liquid, followedby evaporation of the liquid to provide medicament-coated lactosepellets.

For all layering processes it is desirable to restrict the size range ofthe core pellets and hence it may be advantageous to pass the lactosepellets through one or more sieves to remove over or under-size pelletsbefore layering with medicament. Desirably the lactose pellets have adiameter within the range of 50 to 1000 micrometers, particularly 150 to1000 micrometers, for example in the range of 200 to 800 micrometers.

In an alternative embodiment the micronised medicament particles may bepelleted by methods known or analogous to methods known in the art.After pelleting, the medicament pellets may be admixed with the lactosepellets to provide a powder composition according to the invention whichcomprises at least one medicament pellet comprising a plurality ofmicrofine medicament particles and at least one lactose pelletcomprising a plurality of microfine lactose particles, each of saidpellets having a diameter of from about 50 to about 1500 micrometers.

The powder compositions according to the invention optionally containone or more conventional pharmaceutically acceptable ingredients such asdiluents and flavouring agents. The particle size of any suchingredients will preferably be such as to substantially prevent theirinhalation into the bronchial system upon administration of the powdercomposition, desirably in the range of 50 to 1000 micrometers.

The final powder composition desirably contains0.1 to 90% w/w,preferably 1 to 20% w/w of medicament and 10 to 99.9% w/w, preferably 50to 99% w/w of lactose pellets.

It is important that the powder compositions according to the inventionare manufactured, packed and stored under substantially anhydrousconditions. Preferably the powder compositions contain less than 1%,especially less than 0.1% w/w of unbound water.

The compositions according to the invention may conveniently be filledinto a bulk storage container, such as a multi-dose reservoir, or intounit dose containers such as capsules, cartridges or blister packs,which may be used with an appropriate inhalation device, for example asdescribed in GB2041763, WO91/13646, GB1561835, GB2064336, GB2129691 orGB2246299. Such inhalers which contain a composition according to theinvention are novel and form a further aspect of the invention. Thecompositions of the invention are particularly suitable for use withmulti-dose reservoir-type inhaler devices in which the composition ismetered e.g. by volume from a bulk powder container into dose-meteringcavities. The lower limit of powder delivery which may be accuratelymetered from a multi-dose reservoir-type inhaler device is in the regionof 100 to 200 micrograms. The formulations of the present invention aretherefore particularly advantageous for highly potent and hence low dosemedicaments which require a high ratio of excipient for use in amulti-dose reservoir-type inhaler device.

Dry powder inhalers are designed to deliver a fixed unit dosage ofmedicament per actuation, for example in the range of 10 to 5000micrograms medicament per actuation, preferably 25 to 500 micrograms.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularmedicament used and the frequency of administration and will ultimatelybe at the discretion of the attendant physician. When combinations ofmedicament are employed the dose of each component of the combinationwill in general be that employed for each component when used alone.Typically, administration may be one or more times, for example from 1to 8 times per day, giving for example 1,2,3 or 4 unit doses each time.

Thus, for example, each actuation may deliver25 micrograms salmeterol,100 micrograms salbutamol, 25, 50, 125 or 250 micrograms fluticasonepropionate or 50, 100, 200 or 250 micrograms beclomethasonedipropionate.

Crushing Test

A number of tests for the friability (strength or internal coherence) ofpellets or granules have been described in the literature, see forexample GB1520247 and Ganderton & Hunter (1971), J.Pharm.Pharmacol 23,Suppl. 1S-10S, and instrumentation specifically devised for this purposeis now available, for example from Etewe GmbH, Karlsruhe. A simplemethod was devised and used to assess the crushing weight of pelletsaccording to the invention.

Thus, a single pellet was placed on a marked centre position on a baseslide and viewed from above through a stereomicroscope. Microscopy glasscoverslips were used as weights, either 22 mm square (mean170 mg, SD 4mg) or 16 mm circular (mean 75 mg, SD 4 mg). The first weight wassupported at one side and released by sliding the support awaylaterally. Any free-fall was minimised by standardising the pelletdiameter. When a single weight did not fracture or crush the pellet,further weights were applied sequentially.

Weak pellets characteristically showed crushing of the upper surface anda sharp diametric break, at mean crushing weights of less than 500 mg,preferably less than 250 mg.

The invention is illustrated by the following examples.

EXAMPLE 1 Lactose Pellets

Micronised lactose monohydrate (2 g) was placed in a tubular glassscrew-cap scintillation vial and acetone (1.2 ml) was applied to theheadspace walls to avoid localised overwetting. The vial was cappedimmediately and rotated by hand at 45° to the vertical to give suitablepowder flow to induce balling. An occasional sharp tap on the bench wasneeded to dislodge powder adhering to the vial or forming largeagglomerates. As soon as all free powder had disappeared the pelletswere immediately stored over silica gel.

EXAMPLE 2 Lactose Pellets

Micronised lactose monohydrate (50 g) was placed in a cylindrical glasspelletising pan of 160 mm diameter and 80 mm depth, tapering towardsentry, with an axial driving spindle mounted on the flat base. The panwas mounted in the driving chuck of an electric motor at 45° to thevertical and run at 30 rpm (peripheral angular velocity=0.25 ms⁻¹). Thisarrangement gave the required flow pattern in which the powder climbedand then flowed down over a wide region of the flat base of the pan. Acoarse liquid spray of CFC-113 (30 ml) was generated with a “Polyspray2” (Hozelock) spray gun after pressurising the tank initially with 60actuations of the hand air pump. The pellets were tumbled for 5 minutesin the closed pan and then immediately stored over silica gel.

EXAMPLE 3 Coated Lactose Pellets

Lactose pellets prepared according to Example 2 were sieved throughstainless steel sieves to provide a fraction of pellet size 355-500 μm.Sieved lactose pellets (2 g) were mixed with micronised salmeterolxinafoate (100 mg) and then the mixture was placed in a scintillationvial. CFC-113 (60 μl) was applied to the headspace walls, the mixturetumbled as described in Example 1, air dried for 2 minutes and thepellets were immediately stored over silica gel. The oversize fractions(>500 μm) were removed by sieving.

The drug was determined to be uniformly distributed and the layeredpellets were weak as required and gave good respirable drug deliveryi.e. redispersion when tested e.g. for delivery from a Turbohalerinhalation device as measured by the twin impinger assay. As used hereinreference to the “twin impinger assay” means “Determination of thedeposition of the emitted dose in pressurised inhalations usingApparatus A” as defined in British Pharmacopaeia 1988, pages A204-207,Appendix XVIIC.

EXAMPLES 4 TO 6 Lactose Pellets

Lactose pellets were prepared as described in Example 1 using eithercyclohexane, acetone or CFC-113: absolute ethanol (50:50 v/v) in placeof CFC-113.

EXAMPLE 7 Lactose Pellets

Micronised lactose monohydrate (approx 5 g) was shaken by hand over a710 μm aperture sieve to produce friable lactose pellets.

EXAMPLE 8 Lactose Pellets

Micronised lactose monohydrate (1 g) was tumbled in a rotating glassvial for 20 minutes to produce friable lactose pellets (42% in sieverange250-710 μm).

What is claimed is:
 1. A pharmaceutical powder composition suitable forinhalation comprising microfine particles of medicament and at least onelactose pellet having a diameter of from about 10 to about 1500micrometers, which pellet comprises a plurality of microfine lactoseparticles.
 2. A pharmaceutical powder composition according to claim 1,wherein said at least one lactose pellet has a diameter of from about150 to 1000 micrometers.
 3. A pharmaceutical powder compositionaccording to claim 1, wherein at least about 90% by weight of themicrofine particles of lactose have a diameter of less than about 15micrometers.
 4. A pharmaceutical powder composition according to claim1, wherein said at least one lactose pellet is hard or soft.
 5. Apharmaceutical powder composition according to claim 4, wherein the softlactose pellet has a crushing weight of about 50 to about 500 mg asdetermined by the crushing test described herein.
 6. A pharmaceuticalpowder composition according to claim 5, wherein the soft lactose pellethas a crushing weight of about 50 to about 100 mg as determined by thecrushing test described herein.
 7. A pharmaceutical powder compositionaccording to claim 1, wherein the medicament is selected from the groupconsisting of anti-allergies, bronchodilators, anti-inflammatorysteroids and mixtures thereof.
 8. A pharmaceutical powder compositionaccording to claim 1, wherein the medicament is salmeterol xinafoate. 9.A pharmaceutical powder composition according to claim 1, wherein themedicament is salbutamol sulphate.
 10. A pharmaceutical powdercomposition according to claim 1, wherein the medicament is fluticasonepropionate.
 11. A pharmaceutical powder composition according to claim1, wherein the medicament is beclomethasone dipropionate or aphysiologically acceptable solvate thereof.
 12. A pharmaceutical powdercomposition according to any preceding claim, wherein the microfineparticles of medicament form at least one medicament pellet.
 13. Aprocess for preparing a pharmaceutical composition according to claim 1,comprising admixing microfine particles of medicament with at least onelactose pellet having a diameter of from about 10 to about 1500micrometers, which pellet comprises a plurality of microfine lactoseparticles.
 14. A process according to claim 13, wherein the admixingcomprises coating the lactose pellets with a liquid suspension orsolution of medicament.
 15. An inhalation device comprising apharmaceutical powder composition according to claim
 1. 16. Acomposition according to claim 1, wherein the medicament is selectedfrom the group consisting of anti-allergics, bronchodilators,anti-inflammatory steroids and mixtures thereof, for use in thetreatment of respiratory disorders.
 17. A method of treating respiratorydisorders which comprises administration by inhalation of an effectiveamount of a pharmaceutical powder composition which comprises microfineparticles of medicament selected from the group consisting ofanti-allergics, bronchodilators, anti-inflammatory steroids and mixturesthereof and at least one lactose pellet having a diameter of from about10 to about 1500 micrometers, which pellet comprises a plurality ofmicrofine lactose particles.
 18. A pharmaceutical powder compositionaccording to claim 1, wherein said at least one lactose pellet has adiameter of from about 150 to 1000 micrometers, and wherein at leastabout 90% by weight of the microfine particles of lactose have adiameter of less than about 15 micrometers.
 19. A pharmaceutical powdercomposition according to claim 18 wherein the soft lactose pellet has acrushing weight of about 50 to about 500 mg as determined by thecrushing test described herein.
 20. A pharmaceutical powder compositionaccording to claim 19, wherein the medicament is selected from the groupconsisting of salmeterol, xinafoate, salbutamol sulphate, andfluticasone propionate.
 21. A pharmaceutical powder compositionaccording to claim 7, wherein the medicament is selected from the groupconsisting of salmeterol, xinafoate, salbutamol sulphate and fluticasonepropionate.
 22. A pharmaceutical powder composition according to claim1, wherein said at least one lactose pellet has a diameter from about150 to 1000 micrometers and wherein at least about 90% by way of themicrofine particles of lactose have a diameter of less than about 15micrometers and wherein the lactose pellet is a soft lactose pellethaving a crushing weight of about 50 to about 500 mg as determined bythe crushing test described herein.
 23. A pharmaceutical powdercomposition according to claim 22, wherein the soft lactose pellet has acrushing weight of about 50 to about 100 mg.